Lung diseases are the leading cause of mortality in the U.S. Current therapy mainly relies on short-term pharmacotherapy and lung transplantation with limited sustained clinical benefit. Stimulating propagation of alveolar epithelial cells (AECs could increase the lung's capacity to undergo self-repair. Nevertheless, AEC expansion in a diseased lung is frequently handicapped by the lack of epithelially-active cues from the dysfunctional surrounding microenvironmental/niche cells. Consequently, impaired lung repair often provokes excessive scar formation and fibrosis that might inhibit epithelial expansion. We have shown that surgical removal of left lung lobe (pneumonectomy) in mice causes compensatory re-alveolarization in the right lungs. This alveolar regeneration is stimulated by platelets and pulmonary capillary endothelial cells (PCECs). Following pneumonectomy (PNX), platelets deposited in the right lungs upregulate membrane-type metalloproteinase MMP14 in PCECs to stimulate the proliferation of alveolar epithelial stem/progenitor cells such as type 2 AECs (AEC2s). Thus, platelets upregulate epithelially active MMP14 in PCECs to elicit alveolar regeneration. Since this hemo-vascular niche is readily accessible to the circulation, it represents an attractive target to enable therapeutic lung repair. Endothelial MMP14 stimulates AEC expansion by releasing the ectodomain of transmembrane heparin-binding EGF (HB-EGF) that activates EGF receptor (EGFR). Pilot data suggest that MMP14 localized in endothelial cell caveolae blocks lung fibrosis via liberating anti-fibrotic molecule cysteine-rich protein 61 (Cyr61 from extracellular matrix. Caveolar enrichment of MMP14 is induced by platelet-mediated fibroblast growth factor receptor 1 (FGFR1) activation in PCECs. Thus, we hypothesize that MMP14 in the endothelial cell caveolae promotes lung regeneration and blocks fibrosis. To test this hypothesis, we will use mouse pneumonectomy and lung fibrosis model induced by repeated intratracheal injection of Bleomycin to 1) define how endothelial MMP14 processes HB-EGF and Cyr61 to regulate lung regeneration and fibrosis; 2) investigate FGFR1-dependent regulation of MMP14 function. Moreover, we also aim to combine PCEC-targeted gene transduction system and platelet infusion to direct MMP14 in the caveolae of PCECs to promote lung regeneration and prevent fibrosis. This study will help to elucidate how microenvironmental cues such as endothelial MMP14 modulate lung regeneration and fibrosis. Positive outcome of the proposed experiments will help to design a niche-targeted regenerative therapy to facilitate functional lung repair without fibrosis.